Some breast cancer cells require estrogen as a growth factor, the estrogen acting by binding to estrogen receptors on the cancer cells. Compounds which act as competitive estrogen receptor antagonists bind to the estrogen receptor without triggering the estrogen response, and can competitively block binding by native estrogen. Drugs which act through the competitive estrogen antagonism pathway have been successfully used to treat breast cancer.
Tamoxifen is an anticancer drug which has been used for over 40 years to reduce the risk of occurrence or recurrence of cancers, primarily breast cancer. Tamoxifen acts via estrogen receptor antagonism, but tamoxifen itself is actually a prodrug, and in its parent form has moderate to low affinity for the estrogen receptors in breast tissue. Tamoxifen's efficacy relies on metabolism in the liver by cytochrome P450 isoforms CYP2D6 and CYP3A4 to transform tamoxifen into the active metabolites, 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen). Some patients do not respond to tamoxifen treatment because they do not produce adequate amounts of afimoxifen and endoxifen, sometimes due to low levels of the metabolizing enzymes. Giving the active (Z)-endoxifen form directly to tamoxifen non-responsive patients has been shown to result in significantly higher endoxifen blood levels compared to giving a similar dose of tamoxifen, and shows evidence of tumor regressions as shown in a phase I study.
Endoxifen exists as two forms, E and Z, with the Z form more active at the estrogen receptor. Endoxifen is frequently synthesized as a mixture of E and Z, with a difficult separation of isomers required to obtain pure Z isomer. Some procedures in the art separate the E and Z isomers via methods which are expensive and difficult to perform on larger scale, such as preparative HPLC. Thus there is a need in the art for a practical, scalable synthesis that gives access to highly pure (Z)-endoxifen.